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N Engl J Med. 2012 Sep 20;367(12):1087-97.

Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.

Collaborators (295)

Fox RJ, Phillips J, Hutchinson M, Havrdova E, Kita M, Wilson K, Yang M, Dawson KT, Antel J, Ware J, Polman C, Kowey PR, Chung R, Bakris G, Richert J, Seibert B, Brandes D, Brassat D, Cohen B, Diem R, Goldman M, Herndon R, Miller A, Tumani H, Alfaro-Vidal T, Crespo C, Foster J, Hunter K, Garcia-Gomez A, MacManus D, Miller D, Santana V, Tozer D, Kingshott-Wheeler C, Yousry T, Kneebone C, Fedulau A, Mikhailova E, Likhachev S, Naumova H, Vande Gaer L, Decoo D, Sindic C, Grgic S, Sinanovic O, Suljic EM, Georgiev D, Haralanov L, Ivanova S, Minchev D, Tournev I, Stamenova P, Deleva N, Zahariev Z, Manchev I, Vacheva E, Bar-Or A, Kremenchutzky M, Veloso F, Witt N, Blevins G, Parajeles Vindas A, Vargas Howell R, Soldo-Butković S, Rudež J, Habek M, Vurdelja RB, Havrdova E, Doležil D, Vaclavik D, Nova'k J, Gross-Paju K, Antsov K, Haldre S, Palu A, Toomsoo T, Camu W, Pelletier J, Labauge P, Debouverie M, Defer G, De Seze J, Moreau T, Al Khedr A, Rumbach L, Daskalovska V, Landefeld H, Masri S, Schimrigk S, Tackenberg B, Eisensehr I, Hoffmann F, Kieseier B, Lüer W, Benes H, Paschen C, Derfuß T, Sailer M, Storch-Hagenlocher B, Berthele A, Oschmann P, Angnstwurm K, Hohlfeld R, Reifschneider G, Tiel-Wilck K, Nelles G, Boldt HJ, Emrich P, Kallmann BA, Feneberg W, Christopher A, Hüntemann R, Spiegel-Meixensberger M, Thomaides T, Vlaikidis N, Karageorgiou C, Papathanasopoulos P, Mehndiratta MM, Vijayan K, Arjundas D, Srinivasa R, Ghosh A, Kulkarni RV, Shah SD, Mukherji JD, Nellikunja S, Behari M, Singh G, Ghosh P, Ichaporia NR, Sethi PK, Mehta NA, Misra UK, Singh MK, Khurana D, Salem A, Hutchinson M, Sweeney B, Gilad R, Shahien R, Paegle A, Punzo G, Santos J, Quiñones S, Macias MA, Estañol B, Escamilla J, Lopez N, Renteria M, Delgado C, Odainic O, Groppa S, Gavriliuc M, Timmings P, Drozdowski W, Fryze W, Kochanowicz J, Kaminska A, Selmaj K, Wajgt A, Kleczkowska M, Nowacki P, Czlonkowska A, Stelmasiak Z, Podemski R, Dorobek M, Hertmanowska H, Pierzchala K, Zielinski T, Szczudlik A, Tutaj A, Losy J, Potemkowski A, Nyka W, Kapelusiak-Pielok M, Ionescu-Dimancea V, Balasa R, Mihancea P, Popescu C, Protosevici LC, Vojinovic S, Drakulić SM, Raicevic R, Nadj C, Turčáni P, Kahancová E, Kurca E, Lisý L, Montalbán X, Izquierdo G, Arroyo R, Prieto JM, Fernández O, Oreja-Guevara C, Sanchez Lopez F, Guijarro C, Voloshina N, Pasyura I, Palamar B, Nehrych T, Kobys T, Lytvynenko N, Goloborodko A, Buchakchyys'ka N, Lebedynets V, Ryabichenko T, Kushnir G, Moskovko S, Chmyr G, Forester M, Ayala R, Voci J, Krolczyk S, Glaun B, Smith R, Crowell G, Kinkel RP, Patel M, Miller T, Pardo G, Asher S, LaGanke C, Ayres D, Baker M, Williams M, Sheremata W, Vasquez A, Janicki M, Garmany G Jr, Hull R, Steiner D, Herbert J, Edwards K, Fox R, Khatri B, Levin M, Mattson D, Applebee A, Phillips J Jr, Picone MA, Felton W 3rd, Fox E, Apperson M, Gold S, Kita M, Moses H Jr, Shin R, Rinker J 2nd, Hutton G, Krupp L, Fodor P, Foley J, Gazda S, Honeycutt W, Mitchell G, Sadiq S, Steingo B, Jacobs D, Freedman S, Weinstock-Guttman B, Lynch S, Vaishnav A, Wray S, Hunter S, Luzzio C, Huddlestone J, Cohan S, Chinea A, Giang D, Shubin R, Negroski D, Perel A, Stein M, Herskowitz A, Warach J, Mikol D, Bomprezzi R, Eubank G, Licht J, Sullivan H, Rao T, Newman S, Silverman S, Gudesblatt M, Sunter W Jr, Minagar A, Rammohan K, Gottesman M, Schaeffer J, Carlini W, Stein L, Buckler R, Azizi S, Bauer B, Ford C.

Author information

  • 1Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH 44195, USA. foxr@ccf.org

Erratum in

  • N Engl J Med. 2012 Oct 25;367(17):1673.

Abstract

BACKGROUND:

BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate).

METHODS:

In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate.

RESULTS:

At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.

CONCLUSIONS:

In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).

Comment in

PMID:
22992072
[PubMed - indexed for MEDLINE]
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